CHASING SHADOWS: The Search For Clarity

Kayla Pamela dela Cerna, MD; Estherly Grace Gonzales, MD; Aaron Ciel Perez, MD; Bernadette Diane Vista, MD; Oliver Allan C. Dampil, MD; Ronald A. Vallar, MD; John Dave Omolida, MD 

Introduction

Insulinoma is a rare pancreatic neuroendocrine tumor caused by hypersecretion of insulin by B-cells. Preoperative tumor localization may become challenging and may be missed when tumors are too small to be detected by imaging. This case highlights the importance of early tumor detection and endoscopic ultrasound’s value in facilitating diagnosis and localization of small insulinomas.

Case Presentation

A 74-year-old female came in due to recurrent episodes of hypoglycemia, manifesting as dizziness, syncope, hunger, and diaphoresis. She had an episode of sudden loss of consciousness for which she was admitted to a local hospital and was noted to have a capillary blood glucose level of 40 mg/dL. During admission, she had documented hypoglycemic episodes, with the lowest at 25 mg/dL associated with altered sensorium, with regain of consciousness after administration of intravenous glucose. She also manifested hunger, dizziness, and sweating, all relieved by food intake.

Her biochemical test results (Table 1) revealed hyperinsulinemic hypoglycemia.  Suspecting an insulin-secreting pancreatic tumor, whole abdominal CT and MRI scans were performed to locate the tumor, however, both did not reveal any lesion (Table 2).

Table 1. Initial Biochemical Test Results

Table 2. Initial Imaging Results

Due to the recurrent hypoglycemic episodes, the patient underwent an endoscopic ultrasound (EUS) revealing a hypoechoic to an almost anechoic well-defined lesion at the body of the pancreas measuring 0.35cm.

Figure 1. Endoscopic ultrasound. Hypoechoic to almost anechoic well-defined lesion at the body of pancreas measuring 0.35 cm.

Fine needle aspiration biopsy revealed a round cell neoplasm with immunohistochemical staining that was positive for Synaptophysin and Chromogranin. The Ki67 was low at 1.3% and SMAD 4 retained nuclear expression. The overall low-grade cytologic features of the cells of interest and  immunohistochemical staining results support the diagnosis of a Grade 1 well-differentiated neuroendocrine tumor.

Figure 2. Histopathology and Immunohistochemical stains. A-B. Hypercellular smears and cell blocks, showing atypical cells in small clusters, groups, and syncytia. C. Cells of interest were positive in cytoplasmic brown staining for synaptophysin and chromogranin A. D. Rare cells have demonstrated nuclear expression (those with brown stain) specifically at 1.3%. E. Retained nuclear expression of SMAD-4 as shown by the brown stain, ruling out the diagnosis of pancreatic adenocarcinoma.

The patient underwent pancreatic enucleation with complete excision of the tumor. Frozen section was consistent with a neuroendocrine tumor. The tumor size was 0.3cm and was confined to the pancreas. There was resolution of symptoms after surgery.

Figure 3. Pancreatic Body Mass. A. Gross Description: Red, tan, soft tissue fragment measuring 0.7 x 0.5 x 0.5cm. Entire specimen subjected to frozen section and subsequently blocked in one cassette. B. Surgical Histopathology. Well-differentiated neuroendocrine tumor, GRADE 1, Functional; Clinically consistent with Insulinoma; Mitosis: <2 mitosis/2mm; Tumor size: 0.3 cm; The tumor was confined to the pancreas and completely excised; There was no lymphovascular or perineural invasion.

The patient followed up after two weeks with no recurrence of symptoms. To rule out MEN1, additional tests were conducted (Table 3). The patient was advised to undergo genetic testing for MEN1 since the patient satisfied the clinical criteria for MEN1.

Table 3. Test Results

Figure 4. Pituitary MRI. Small hypoenhancing pituitary gland lesion measuring 3.3 x 2.2 x 1.7 mm. Primary Consideration is Pituitary Micoradenoma.

Discussion

Insulinomas are rare hormone-producing pancreatic neuroendocrine neoplasms (panNEN), with an incidence of 0.7 to 4 cases per million per year. They are most commonly found in the pancreas, with a peak incidence in the fifth decade of life for men and the sixth decade for women. Insulinomas are slightly more common in women than in men. While most insulinomas are located in the pancreas, occasionally they can be found in other areas such as the lung, duodenum, ileum, jejunum, hilum of the spleen, and gastric antrum. Approximately 10% of insulinomas present as multiple lesions.

Patients with insulinomas generally exhibit Whipple’s triad, with symptoms such as plasma glucose <50mg/dl, neuroglycopenic symptoms, and relief of symptoms after glucose administration. A 72-hour fast is the gold-standard test for diagnosing insulinoma. The combination of plasma glucose under 55 mg/dL, plasma insulin > 3 microUnits/mL, C peptide > 0.6 ng/mL, proinsulin > 5 pmol/L, beta-hydroxybutyrate > 2.7 mmol/L, and a simultaneous negative sulfonylurea screen indicates hypoglycemic hyperinsulinemia.

A local 5 year-review of endocrine malignancies in 2014 showed 2 cases of malignant insulinomas out of 855 cases of endocrine cancers. Currently, seven case reports of insulinomas from the Philippines have been published. Most were females with tumor sizes ranging from 0.5 cm to 12 cm.

Table 4.

Preoperative localization of insulinomas is important but may be challenging since approximately 30% are less than 10 mm in diameter. CT scan is widely used as first-line imaging because of its availability and high spatial resolution. It has a sensitivity of 54% and a specificity of 75% in localizing insulinomas. MRI is an alternative when CT scans are inconclusive, offering better soft-tissue resolution without radiation. It has a detection sensitivity of 54% and specificity of 65%.

In cases where both MRI and CT scans are normal, endoscopic ultrasound (EUS) can be used. EUS consistently increased the detection of PNETs by over 25%. It has a pooled detection sensitivity of 81% and specificity of 90%.

The EUS performed in our patient, revealed a pancreatic tumor measuring 0.35 cm, which is six times smaller than the previously documented smallest tumors.

Surgical removal is the main treatment for insulinomas, and the procedure depends on the size and location of the tumor. Small insulinomas are typically removed through tumor enucleation. After surgery, most patients experience symptom relief and are cured of the disease. However, there may be some postoperative effects such as rebound hyperglycemia and weight loss. Postoperative hyperglycemia has been linked to the hormonal effects of glucagon, growth hormone, and glucocorticoids in the immediate postoperative period, and it typically resolves within a few days. Some patients may develop postoperative diabetes mellitus, contributing to persistent hyperglycemia that requires treatment, and weight loss has been reported in some cases.

Some case reports mentioned weight loss over a specified amount of time after surgery. The weight loss pattern may not be generalizable, but rapid weight loss can occur on the 19th to 39th day after surgery.

Around 5 to 10% of insulinomas are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome, which presents with various endocrine and non-endocrine tumors due to genetic mutations. MEN1 can be diagnosed based on clinical, familial, or genetic criteria, and patients may need genetic testing to confirm the diagnosis.

Conclusion

Symptoms such as loss of consciousness, hypoglycemia, and weight gain should raise suspicion of hyperinsulinemic hypoglycemia. Insulinoma, a rare neuroendocrine tumor, is typically benign but can be life-threatening. Studies have shown that tumor size does not necessarily correlate with disease severity. Locating small tumors before surgery can be challenging and they might not be detected by imaging. Even if imaging doesn’t show any specific pancreatic lesions, the possibility of a pancreatic mass should not be ruled out. Surgical removal is the preferred treatment due to its high success rate, while medical therapies are used for tumors that can’t be operated on or have spread. MEN1 should be considered in patients with insulinoma as it can be the first sign in 15% of cases.

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